Device for removing bacterial lipopolysaccharides and/or lipoteichoic acids from protein-containing fluids and its use for the treatment of sepsis

ABSTRACT

A device for removing bacterial lipopolysaccharides and lipoteichoic acids from blood or plasma in an extracorporeal perfusion system contains, in a housing that can be incorporated into the perfusion system, a hollow fiber material that is suitable for the selective removal of bacterial lipopolysaccharides and lipoteichoic acids, the device being arranged in such a way that the blood or plasma entering through a first opening of the housing must pass through the hollow fiber material before it leaves through a second opening of the housing and is directed to the rest of the perfusion circuit.

The present invention relates to a device for removinglipopolysaccharides (LPS, endotoxins) and/or lipoteichoic acids (LTA)from protein-containing fluids, especially from blood or plasma, and theuse of the said device for the treatment of patients with diseases thatare caused by the invasion of gram-negative and/or gram-positivebacteria.

When there is bacteremia in the human bloodstream, serious, so-calledseptic complications or disease courses can often develop.

In 50 to 95% of patients with severe sepsis or septic shock, a lethaloutcome is to be expected despite all therapeutic measures (Stone, R.,Science (1994) 264: 365-367). There has been a significant increase inthe incidence of sepsis in recent years. The reasons for this includethe increasing diagnostic and therapeutic use of catheters, endoscopes,implants of prostheses, major surgery, the use of immunosuppressants,the increased number of elderly patients and bacteria's increasingresistance to antibiotics. Infections of patients in intensive care arenowadays caused primarily by resistant bacteria (Vincent, I. L., JAMA(1995) 274: 639-644).

The endotoxins (lipopolysaccharides, LPS) released during and afterbacteriolysis and drug-induced antibiosis are mainly responsible for thepathogenicity of the gram-negative bacteria.

Lipopolysaccharides, as constituents of the outer membrane ofgram-negative bacteria, are made up of three structurally differentregions. The carrier of the toxic properties is lipid A. This subregionwith a molecular weight of 2000 dalton consists of a phosphorylatedD-glucosamine disaccharide, to which several long-chain fatty acids arebound in the form of esters and amides (Bacterial EndotoxicLipopolysaccharides, Morrison, D. C., Ryan, J. L. eds., 1992, CRCPress). The bacterial lipopolysaccharides (LPS) are the initiatingmediators and principal toxins in the pathogenesis of septic shock. Theclinical picture of sepsis often correlates with the level of the LPSconcentration in the patients' blood (Nitsche, D. et al., Intensive CareMed., 12 Suppl., 1986, 185 ff). The lipopolysaccharides stimulate thebody's phagocytes, called macrophages, to produce and releaseinflammatory mediators such as TNF α and interleukins.

Removal of LPS in particular, but also of the endogenous inflammatorymediator TNF α, has therefore been the approach for treating sepsispatients up till now.

It has been established, however, that not only the LPS of thegram-negative bacteria play a large part, but also that infections bygram-positive bacteria, which do not contain any LPS, lead to septiccomplications, and in particular the dangerous hospital germs such asStaphylococcus aureus have proved particularly pernicious.

Almost 50% of sepsis patients have an infection with gram-positivebacteria. About 30% of the patients have a mixed bacterial infection.

The toxins of the gram-positive bacteria, the lipoteichoic acids (LTA),are also located in the cell wall and are released during lysis of thebacteria. The LTA consist of glycerol or ribitol polymers, which arelinked to glycolipids or phosphatidyl glycolipids via 1→3 phosphodiesterbends. The polyglycerol or ribitol chains additionally carry glucoseand/or N-acetylglucosamine residues. The LTA stimulate, similarly to theLPS, monocytes and other immunocompetent cells to produce cytokines(Mattson, T., FEMS Immunol. Med. Microbiol. (1993) 7: 281-288). Thedeleterious biological mediator cascade is mediated or triggered, aswith LPS, via soluble and membrane-bound receptors that are present inthe bloodstream (Cleveland M. G., Infect. Immun. (1996) 64: 1906-1912).

LTA flowing into the bloodstream binds to the cells of themonocyte-macrophage system and stimulates the latter to increasedproduction and release of mediators (cytokines). As the initial mediatorand potent pro-inflammatory stimulus, first the tumor necrosis factor ais synthesized and secreted into the bloodstream. The biologicallyactive form of TNF a consists of an aggregate of three identicalpolypeptide chains (157 amino acids, molecular weight: 17.4×10³ dalton;Ziegler, E. J., N. Engl. J. Med. 318 (1999) 1533 ff). The subsequentbiological signal amplification via interleukins, leukotrienes,prostaglandins and interferons (mediator cascade) can finally causesevere disturbances of homeostasis of various biological control systemsand organ systems, for example the clinical picture of septic shock.

Accordingly, the lipopolysaccharides (LPS) as initiating toxins ofgram-negative bacteria and the lipoteichoic acids (LTA) as highly potentpyrogens of gram-positive bacteria, play a key role in the pathogenesisof sepsis.

Alongside removal of the septic focus by surgery and the administrationof antibiotics, new therapeutic approaches that go beyond sanitation ofthe source of sepsis, such as plasmapheresis, and the administration ofimmunoglobulins and antibodies against LPS (Bone, R. C., Crit. Care Med.(1995) 23: 994-1000) or TNF α (Fisher, C. J., N. Engl. J. Med. (1996)334: 1697-1702) have not provided a substantial improvement in theprognosis for a sepsis patient.

Plasmapheresis (plasma replacement treatment) is an unselective andinefficient technique. As well as eliminating toxins andpro-inflammatory cytokines, protective, anti-inflammatory mediators arealso removed from the patient. A single cycle of therapy requires areplacement volume of approx. 12 liters of plasma. Accordingly, about 50donors are needed, and this involves an increased risk with respect toadditional infections and allergic reactions.

Antibody therapy methods also have serious deficiencies anddisadvantages. The costs of the technically expensive extraction,purification and characterization of the relevant antibodies are veryhigh and there is the risk of allergic reaction (neutralizing immuneresponse) of the body to the antibodies. With regard to LPS antibodies,the high rates of failure of therapy can be attributed among otherthings to the excessively low specificity and affinity between the veryheterogeneous LPS molecules and the monoclonal and polyclonal antibodiesused. In this connection, multicenter clinical studies had to beterminated early (Luce, J. M., Crit. Care Med. 21 (1993), 1233 ff).

Another procedure for the neutralization or elimination of pathogenicblood components consists of treating whole blood or plasma in anextracorporeal perfusion system using appropriate adsorbent materials.

The following adsorbent materials have been disclosed as potentiallysuitable for extracorporeal elimination of lipopolysaccharides fromwhole blood and/or plasma:

Porous carrier materials with immobilized polymyxin B are described inU.S. Pat. No. 4,576,928; DE 39 32 971. However, the clinical applicationof these affinity carriers is very problematic, because the ligandpolymyxin B causes severe nephro- and neurotoxic damage on its releaseinto the bloodstream.

The polyethylene-imine-modified bead celluloses disclosed in DE 41 13602 A1 have very low binding capacity for LPS. If they are used in anextracorporeal perfusion system, therefore, the medically tolerableextracorporeal dead volume would be exceeded.

The H.E.L.P method described for the elimination of LPS and TNF a (DE 4435 612 A1) is complex and therefore imposes high requirements on itsoperation in an intensive care unit. The system requires a very largeextracorporeal dead volume and therefore, for hemodynamic reasons, isless advantageous for the patient being treated. Another disadvantage ofthis plasma perfusion technique is that in addition to LPS and TNF α,fibrinogen—which is essential for plasma coagulation—is also eliminatedvery effectively. Therefore, depending on the starting concentration offibrinogen, use of the H.E.L.P. method is limited to a maximum of 2-3consecutive treatments, which is in many cases insufficient foreffective treatment of the patient.

Compared with the anion exchanger material described in Example 2 of DE195 15 554 A1, the hollow fiber-based anion exchanger materialspresented in the present invention have the advantage that they cannotrelease any glucans. The latter disturb the analytical detection ofbacterial endotoxins in the patient's plasma. Furthermore, glucans cancause unwanted hemolysis and unwanted immune stimulation in the patient.

The present invention was based on the problem of providing a possibletreatment and a suitable device therefor, with which the disadvantagesof the methods employed to date can be avoided, and which permiteffective treatment of sepsis patients in general, regardless of thetype of causative bacteria.

This problem is solved according to the invention with a device forremoving bacterial endotoxins and lipoteichoic acids from blood orplasma in an extracorporeal perfusion system, comprising a hollow fibermaterial suitable for selective removal of bacterial endotoxins andlipoteichoic acids, in a housing that can be incorporated in theperfusion system. The device according to the invention is arranged sothat blood or plasma entering through a first opening in the housingmust pass through the hollow fiber material before it leaves the housingthrough a second opening and rejoins the perfusion circuit.

For such a device to be used for adsorption apheresis, among otherthings the following conditions must be met:

-   1. Elimination of pathogens should be as selective and efficient as    possible.-   2. The binding capacity of the adsorbents used should satisfy    optimum practical requirements.-   3. It must be possible to sterilize the adsorbents with heat or    gamma radiation, without loss or alteration of their properties.-   4. The adsorbents should permit a sufficiently high flow rate of up    to 200 ml/min.-   5. The method of elimination must display the medically necessary    biocompatibility and hemocompatibility and must not impair any    physiological control systems and protective mechanisms, for example    the immune, complement or coagulation system.

A person skilled in the art will be able to find suitable hollow fiberadsorbent materials according to this profile of requirements. Inprinciple, hollow fiber materials can be used that are made frompolyamide, polysulfone, polyether, polyethylene, polypropylene,polyester or derivatives and/or mixtures of these polymers. In anespecially preferred embodiment of the invention the hollow fibersconsist of nylon.

Suitable hollow fiber materials according to the invention are based onaffinity membranes, as described for example in U.S. Pat. Nos.5,053,133, 5,766,908, and in WO96/22316. These membrane base materialscan be modified by known methods and in particular by graftpolymerization, in this connection see for example WO96/22316, in whichan appropriate method is described. Other derivatization methods forappropriate polymer materials, suitable for the production of hollowfiber adsorbent materials, are also known to a person skilled in the artand can be used within the scope of the present invention.

The hollow fiber materials according to the invention are preferablyarranged in the device according to the invention in such a way thatthere is effective flow of blood or plasma through them, ensuringmaximum wetting of the hollow fiber membrane so that optimum adsorptionof the LPS and LTA onto the hollow fiber adsorbent materials can takeplace. Preferred arrangements of the hollow fiber materials in a deviceaccording to the invention are disclosed in WO98/57733, WO98/33581,WO98/19777 or WO98/28064, and an especially preferred arrangement ismoreover described in EP 1 002 566.

As well as the hollow fiber materials, a device according to theinvention can have additional materials, e.g. flat membranes, betweenthe hollow fibers, which can often give a further increase in adsorptionand separation performance. Corresponding adsorber arrangements aredescribed in EP 0 956 147.

Both the materials disclosed in the aforesaid documents and the methodsof modification and ultimate arrangements in adsorbers can be employedin the device according to the invention. Other arrangements, materialsand methods of modification are, however, also included in the presentinvention, provided they permit effective removal of LPS and LTA fromblood and plasma, and otherwise satisfy the aforesaid requirements 1 to5 for adsorption apheresis.

To make the removal of LPS and LTA from blood or plasma particularlyefficient, the device employs hollow fibers that are modified chemicallyin such a way that the charged LPS and LTA molecules are boundparticularly well to the hollow fiber material and are therefore removedfrom the blood or plasma. Preferably, chemical modification of thehollow fiber material is carried out, and graft polymerization (seeabove) has proved especially favorable for the said modification,compounds being grafted onto the hollow fiber material that display goodbinding capacity for LPS and/or LTA. Grafting-on of anion exchangergroups has also proved especially advantageous. These anion exchangergroups are especially advantageous when in the form of longer chainswith a large number of cationic groups, called tentacles. Thesetentacle-like extensions on the base material are able to bind severalLPS or LTA molecules, producing a further increase in efficiency of thehollow fiber material. This modification of the hollow fiber material bymeans of tentacles preferably employs synthetic and/or semisyntheticand/or natural polycationic chains, and the said chains can be in linearor branched form. Modification of the hollow fiber materials accordingto the invention with cationic or polycationic chains that have tertiaryand/or quaternary amines is especially preferred.

Preferred anion exchanger groups on the hollow fiber materials includedi- or trialkylaminoalkyl, di- or trialkylaminoaryl-, di- ortriarylaminoalkyl, di- or triarylaminoaryl, di- ortrialkylammoniumalkyl- di- or triarylammoniumalkyl, di- ortriarylammoniumaryl- and di- or trialkylammoniumaryl residues.Furthermore, polymers from amino acids that are positively charged orcontain tertiary or quaternary amino groups, such as polylysine,polyarginine or polyhistidine or copolymers or derivatives thereof aresuitable as anion exchanger materials within the scope of the invention,as well as polyethylene-imine.

In quite especially preferred embodiments of the invention, the devicecontains a polyamide hollow fiber material modified withdiethylaminoalkyl or diethylaminoaryl residues, in particulardiethylaminoethyl polyamide.

Furthermore, it is preferred to arrange the device in such a way that itcan be used as a replaceable filter cartridge for an existing perfusionsystem. This can be inserted easily into the perfusion system and canhave a small volume, on account of the high binding capacity andspecificity of the hollow fiber material used, so that a greatly reduceddead volume can be achieved in comparison with systems describedhitherto. Surprisingly, a device according to the invention can be madeas a cartridge with dimensions of for example 12 cm long and 5 cm indiameter, which can be used extremely effectively in an extracorporealperfusion system. The cartridge in this example has a dead volume ofonly approx. 115 ml. Therefore it is especially preferred, within thescope of the present invention, to dimension the cartridges so that thedead volume is <150 ml and preferably 80 to 130 ml.

As it could be shown that the said filter cartridges can remove LPS andLTA effectively and selectively, merely this small dead volume providessurprising and considerable advantages relative to the state of the artin addition to the possibility newly discovered according to theinvention, of removing LPS and LTA simultaneously in one implementation.After the end of treatment and cleaning of the apparatus or even forcarrying out an extended (continuous) blood or plasma perfusion, a newcartridge can simply be inserted.

Within the scope of the present invention, it was found that therelevant hollow fiber materials eliminate both LPS and LTA atphysiological pH by adsorption from whole blood and/or blood plasma, athigh selectivity and capacity.

It was found that even at physiological pH, only a small,compositionally safe amount of blood and plasma proteins are adsorbed.Fibrinogen, in particular, is only removed from the patient's blood to aquite small extent (<2%) within the scope of the present invention, sothat there is hardly any impairment of the natural coagulation cascadewhen using the device according to the invention. Owing to theextraordinarily high binding capacity for LPS on the one hand and LTA onthe other hand, the device according to the invention makes it possible,for the first time, to treat sepsis regardless of whether the disease iscaused by gram-positive or gram-negative bacteria, or even if there is amixed bacterial infection.

A further object of the invention is accordingly the use of the hollowfiber materials described, and contained in the device according to theinvention, for making a means for eliminating lipopolysaccharides and/orlipoteichoic acids from body fluids, in particular from blood or plasma.

The hollow fiber materials used according to the invention, which arepreferably selected from the group comprising polyamides, polysulfones,polyethers, polyethylene, polypropylene or polyesters and derivativesand/or mixtures of these materials, permit effective elimination of LPSand/or LTA from a patient's blood circulation and can therefore be usedadvantageously in an adsorption apheresis apparatus. As a rule, in suchapparatus there will firstly be separation of whole blood into plasmaand corpuscular blood components, then the plasma is directed over theadsorbent material and after that the corpuscular blood components arereturned to it.

The hollow fiber materials used as adsorbents according to the inventionare, in a preferred embodiment, modified chemically in such a way thatoptimum LPS or LTA adsorption can take place thereon. Modification ofthe hollow fibers by graft polymerization is especially preferred, andthe grafting-on of anion exchanger groups, especially in the form ofso-called tentacles, i.e. chain-like, branched molecules with as manyanion exchanger groups as possible, is preferred.

An especially preferred hollow fiber material is a DEAE-modifiedpolyamide.

As already mentioned above, with respect to the device according to theinvention, it is advantageous to arrange the means in the form of afilter, if possible in the form of a disposable cartridge, ensuring easyand safe use.

The means produced according to the invention can be used especiallyadvantageously for the treatment of patients with sepsis and especiallywith septic shock, since they remove the bacterial pyrogens from thepatient's blood owing to the good selectivity and specificity for LPSand LTA, without further stimulation of the inflammatory mediatorcascade. Because of the high specificity for LPS and for LTA, it becomespossible to treat patients with the same apparatus and the same means,regardless of whether they are suffering from sepsis caused bygram-positive or gram-negative bacteria or by both types.

The corresponding use of the device according to the invention or of themeans produced according to the invention for removing LPS and/or LTAfrom body fluids, especially blood or plasma, and especially for thetreatment of patients with sepsis even as far as septic shock, istherefore a further object of the present invention. Especiallyadvantageously, the device according to the invention or the meansproduced according to the invention are used in an extracorporealperfusion system, which provides particularly effective removal ofbacterial pyrogens from the patient's blood and leads to exceptionallysuccessful treatment of patients. During application according to theinvention, moreover, LPS and/or LTA are removed very selectively,whereas endogenous proteins are only removed to a very small extent, ifat all, or said removal only applies to proteins that are easilyreplaceable and whose removal is not notably stressful for the alreadymuch debilitated sepsis patient.

Within the scope of the present invention it is also possible to use theadsorbent materials described above for the isolation and enrichment ofLPS and LTA, therefore the said use of the device according to theinvention is a further object of the present invention. The saidisolation and enrichment can take place from any fluids, preferably fromblood or plasma, and this can be done for any purposes, though inparticular for analysis and/or diagnosis.

The invention is explained in more detail in the following examples.

EXAMPLE 1

Adsorption and elimination of LPS from human plasma on perfusion throughthe adsorber module according to the invention

The adsorber module used (length 12 cm, diameter 5 cm) was packed withhollow polyamide fibers according to EP 1 002 566 A2. The surface of thehollow fibers was modified according to the invention, with tentaclesthat were grafted on by polymerization and functionalized with DEAEgroups. The module was first washed and conditioned with 500 ml ofRinger's solution (140 mmol/l NaCl; 2 mmol/l CaCl₂ and 4 mmol/l KCl),prior to perfusion with human plasma.

140 ng (corresponding to approx. 1400 endotoxin units, EU) ofradioactive ³H-LPS (E. coli K12 strain LCD 25) with a specific activityof 4×10⁵ dpm/μg was added to 100 ml of human plasma. This mixture waspumped through the hollow fiber module according to the invention atroom temperature using a peristaltic pump at a flow rate of 20 ml/min,and eluate fractions (5 ml) were obtained every 15 seconds. Subsequentliquid scintillation measurement of radioactivity showed that ³H-labeledLPS could not be detected in any of the fractions obtained.

Quantitative determination of LPS in the perfusate was carried out inparallel using the chromogenic kinetic. Limulus-Amoebocyte-Lysate test(supplier: BioWhittaker). This trace-analysis measurement technique alsoshowed that the LPS added to the human plasma was no longer detectablein the perfusate and therefore had been eliminated completely.

EXAMPLE 2

Adsorption and elimination of LTA from human plasma on perfusion throughthe adsorber module according to the invention

The adsorber module used (length 12 cm, diameter 5 cm) was packed withhollow polyamide fibers according to EP 1 002 566 A2. The surface of thehollow fibers was modified according to the invention, with tentaclesthat were grafted on by polymerization and functionalized with DEAEgroups. The module was first washed and conditioned with 500 ml ofRinger's solution (140 mmol/l NaCl; 2 mmol/l CaCl₂ and 4 mmol/l KCl),prior to perfusion with human plasma.

200 μg LTA from Streptococcus pyogenes (supplier: Sigma-Aldrich) wasadded to 100 ml human plasma, which was then pumped at room temperaturethrough the adsorber module described above by a peristaltic pump at aflow rate of 20 ml/min. 5-ml eluate fractions were obtained at 15-secondintervals and were investigated for LTA activity.

This was carried out using a whole-blood stimulation test. For this, analiquot from each of the eluate fractions obtained was added in a ratioof 6:1 (v/v) to freshly obtained, heparinized whole blood from a healthydonor, which was then incubated at room temperature for 24 hours. Aftercentrifugation, obtaining the corresponding plasma fraction,interleukin-6 (IL-6) was determined quantitatively in all the eluatefractions obtained and incubated, using an ELISA test (supplier:Biosource).

The result found was that none of the perfused plasma fractions led toLTA-mediated stimulation of IL-6 biosynthesis, i.e. to an increased IL-6concentration relative to a control (perfused aliquot of a plasma samplewithout addition of LTA). Therefore, with the aid of this highlysensitive bioassay it was demonstrated, admittedly indirectly, buthighly significantly, that the adsorber module used according to theinvention provides complete elimination of bacterial lipoteichoic acidfrom human plasma.

EXAMPLE 3

Simultaneous adsorption and elimination of LPS and LTA from human plasmaon perfusion through an adsorber module according to the invention

The adsorber module used (length 12 cm, diameter 5 cm) was packed withhollow polyamide fibers according to EP 1 002 566 A2. The surface of thehollow fibers was modified according to the invention, with tentaclesthat were grafted on by polymerization and functionalized with DEAEgroups. The module was first washed and conditioned with 500 ml ofRinger's solution (140 mmol/l NaCl; 2 mmol/l CaCl₂ and 4 mmol/l KC1),prior to perfusion with human plasma.

2000EU of bacterial LPS (E. coli 055: B5 endotoxin; supplier:BioWhittaker) and 100 μg LTA (Streptococcus pyogenes; supplier:Sigma-Aldrich) were added to 100 ml of human plasma.

In accordance with the test procedure in Example 2, correspondingperfusate fractions were obtained and were investigated for any LTA orLPS activity present, using the whole-blood stimulation test described.The analysis showed that LTA or LPS activity could not be detected inany of the perfusates.

1-34. (canceled)
 35. A method of treating sepsis comprising treating apatient with sepsis by passing a body fluid of the patient through adevice comprising a chemically modified hollow fiber material that issuitable for the selective removal of bacterial lipoteichoic acid suchthat the body fluid passes though said hollow fiber material and saidhollow fiber material removes the bacterial lipoteichoic acid from thebody fluid.
 36. The method of claim 35, wherein the hollow fibermaterials used are selected from the group comprising polyamides,polysulfones polyethers, polyethylene, polypropylene or polyesters, andderivatives or mixtures thereof.
 37. The method of claim 35, wherein thehollow fiber material is a polyamide.
 38. The method of claim 35,wherein the hollow fiber material is modified by graft polymerization.39. The method of claim 35, wherein tentacles, which comprise anionexchanger groups, are polymerized onto the hollow fiber material. 40.The method of claim 35, wherein the anion exchanger groups comprise atleast one of a synthetic, a semisynthetic, and a natural polycationicchain, said chain being in linear or branched form.
 41. The method ofclaim 39, wherein the anion exchanger groups comprise cationic orpolycationic chains having tertiary or quaternary amines.
 42. The methodof claim 39, wherein the anion exchanger groups are selected from thegroup consisting of di- or trialkylaminoalkyl, di- or trialkylaminoaryl,di- or triarylaminoalkyl, di- or triarylaminoaryl, di- ortrialkylammoniumalkyl, di- or triarylammoniumalkyl, di- ortriarylammoniumaryl, di- or trialkylammoniumaryl residues, polymers fromamino acids that are positively charged or contain tertiary orquaternary amino groups, and polyethylene-imine.
 43. The method of claim35, wherein the hollow fiber material comprises a polyamide modifiedwith diethylaminoethyl groups.
 44. The method of claim 35, wherein thedevice is arranged in the form of a filter module.
 45. The method ofclaim 44, wherein the filter module has a dead volume of <150 ml. 46.The method of claim 35, wherein the device permits a flow rate of up to200 ml/minute.
 47. The method of claim 35, wherein said device isdesigned for application in a plasma perfusion system.
 48. The method ofclaim 35, wherein said device is suitable for the treatment of diseasescaused by at least one of gram-negative or gram-positive bacteria.
 49. Amethod of treating sepsis comprising treating a patient with sepsis bypassing a body fluid of the patient through a device for removingbacterial lipoteichoic acid from a body fluid, said device comprising ahousing that can be incorporated into the perfusion system, a chemicallymodified hollow fiber material that selectively removes bacteriallipoteichoic acid in the housing, the device being arranged such thatthe blood or plasma entering through a first opening of the housing mustpass through the hollow fiber material before it leaves through a secondopening of the housing and is directed to the rest of the perfusionsystem, wherein said hollow fiber material comprises at least onepolymer selected from the groups consisting of polyamide, polysulfone,polyether, polyethylene, polypropylene, polyester and derivatives andmixtures thereof, wherein said hollow fiber material has tentaclescomprising an anion exchange group polymerized thereon by graftpolymerization, wherein the anion exchange group comprises at least oneof the group consisting of a synthetic polycationic chain, asemisynthetic polycationic chain and a natural polycationic chain,wherein said synthetic, semisynthetic and natural polycationic chainsare linear or branched and wherein said device has a dead volume <150ml.
 50. The method of claim 49, wherein the device is used in anextracorporeal perfusion system.
 51. The method of claim 49, wherein thepatient is afflicted with septic shock.
 52. The method of claim 49,wherein the body fluid is blood or plasma.
 53. The method of claim 49,wherein the device is a replaceable filter cartridge.
 54. The method ofclaim 49, wherein the hollow fiber material comprises nylon.
 55. Themethod as claimed in claim 49, wherein the anion exchange groupscomprise a synthetic polycationic chain.
 56. The method as claimed inclaim 49, wherein the anion exchange groups comprise a cationic chain ora polycationic chain including at least one of a tertiary amine or aquaternary amine.
 57. The method as claimed in claim 49, wherein theanion exchange groups are selected from the group consisting of di- ortrialkylaminoalkyl, di- or trialkylaminoaryl, di- or triarylaminoalkyl,di- or triarylaminoaryl, di- or trialkylammoniumalkyl, di- ortriarylammoniumalkyl, di- or triarylammoniumaryl or di- ortrialkylammoniumaryl residues, polymers from amino acids that arepositively charged or contain a tertiary or a quaternary amino group,and polyethylene-imine.
 58. The method as claimed in claim 49, whereinthe hollow fiber material comprises a polyamide modified withdiethylaminoethyl groups.
 59. The method as claimed in claim 49, whereinthe hollow fiber material permits a flow rate of up to 200 ml/minute.60. The method of claim 39, wherein the anion exchanger groups arepositively charged.
 61. The method of claim 60, wherein the anionexchanger groups are at least one of a tertiary amine or a quaternaryamine.
 62. The method of claim 51, wherein the anion exchanger groupsare positively charged.
 63. The method of claim 53, wherein the anionexchanger groups are at least one of a tertiary amine or a quaternaryamine.